The investigations outlined in this proposal are at the interface between immunology and developmental biology, and are designed to study the differentiative events leading to the development of immunocompetent cells in the mouse embryo. The major emphasis is on the thymus, on thymus-destined, and on thymus-derived cells in the belief that questions of cell recognition are fundamental to most or all of the events associated with developmental interactions. Experiments are described for investigating immunocompetence of yolk sac, liver, and thymus cells in assays such as mixed leukocyte culture, cell-mediated lympholysis, graft-versus-host reaction and lymphocyte-mediated angiogenesis, and as helper cells in the in vitro response to sheep red blood cells. It is proposed to carry out a series of transplantation and culture experiments to resolve the questions of intrinsic versus extrinsic sources of stem cells responsible for developing into the variety of functional thymus subpopulations. Use of genetic variants is contemplated to assist in this analysis. It is proposed to develop a series of serological reagents with specificity for early stem cells and stem cell precursors, and to apply reagents in a critical analysis of the ontogeny of immune responsiveness. Other exploratory projects are also contemplated. It is believed that the project has broad relevance to our understanding of immunological functions as well as of the mechanisms underlying normal developmental processes. Understanding of the development of the immune response seems prerequisite to understanding the nature of autoimmunity, of waning immune responsiveness during the aging process, of the machinery that must be manipulated by cells during oncogenesis to achieve survival and tumor growth in the face of antigenic disparity, and of the problems associated with feto-maternal incompatibility.